Two-Drug Combination Shows Promise Against One Type of Pancreatic Cancer

Two-Drug Combination Shows Promise Against One Type of Pancreatic Cancer

One form of pancreatic cancer has a new enemy: a two-drug combination discovered by researchers that inhibits tumors and kills cancer cells in mouse models. This finding was published in the Journal of the National Cancer Institute (2015; doi:10.1093/jnci/djv123).

For the first time, researchers have shown that a certain protein becomes overabundant in pancreatic neuroendocrine tumors, allowing them to thrive. They also found that pairing a synthetic compound with an existing drug provides a more effective anticancer punch than a single drug. The research team included Rony A. François, an MD/PhD student working with Maria Zajac-Kaye, PhD, an associate professor in the University of Florida College of Medicine's department of anatomy and cell biology in Gainesville.

Finding new treatments is critical because less than 5% of patients with pancreatic neuroendocrine tumors respond to everolimus, the most commonly used pharmaceutical, François said. Neuroendocrine tumors, which form in the hormone-making islet cells, account for 3% to 5% of pancreatic malignancies and have a 5-year survival rate of about 42%, according to the National Cancer Institute.

Pancreatic neuroendocrine tumors are increasingly common, which medical experts and researches have attributed to better diagnostic imaging, an aging population, and heightened awareness of the disease stemming from the 2011 death of Apple Inc. co-founder Steve Jobs.

Zajac-Kaye's group discovered that a single protein is behind the process that allows pancreatic neuroendocrine tumors to thrive. The protein, known as focal adhesion kinase (FAK) activates an enzyme called AKT, which helps islet cells in the pancreas survive. But when islet cells begin turning into tumors, the FAK protein is overproduced, researchers found. This overabundance of the protein allows tumors to resist chemotherapy and evade efforts to kill them off.

After identifying the role of FAK in tumor development, François started looking for ways to keep it in check. One idea was finding something to make the antitumor drug everolimus more effective.

"Once we figured out that FAK was important, we started looking for drug combinations that would increase efficacy," he said.

Among the substances they tested was a synthetic, small-molecule compound known as PF-04554787. During lab testing, the compound markedly inhibited the growth of three human pancreatic cancer cell lines 5 days after treatment and induced the death of pancreatic cancer cells. Researchers then tested its effectiveness on human pancreatic cells that had been implanted in mouse models. Daily doses of the compound reduced tumor volume by approximately 50% after 25 days.

Next, researchers paired the compound with everolimus. While everolimus can extend some patients' lives by holding tumors in check, it does little to make them regress and is not effective for many people. François wondered if the synthetic compound would make everolimus more effective. It did, with the two-drug combination killing off pancreatic cancer cells more effectively than everolimus alone. In testing on two mouse cell lines, the drug combination reduced the viability of cancer cells by about 50% when compared with everolimus alone, according to the findings.

That an existing drug can be made more effective is especially encouraging because the synthetic compound they paired with everolimus is already undergoing human clinical trials, Francois said.

"This is important because we're focused on everolimus, a drug that is already approved, nontoxic and given to patients. Anything that we can do to make it better represents a big improvement," François said.